title: Metal-based inhibition of poly(ADP-ribose) polymerase--the guardian angel of DNA.
abstract: The inhibition activity of a series of anticancer metal complexes based on platinum, ruthenium, and gold metal ions was evaluated on the zinc-finger protein PARP-1, either purified or directly on protein extracts from human breast cancer MCF7 cells. Information on the reactivity of the metal complexes with the PARP-1 zinc-finger domain was obtained by high-resolution ESI FT-ICR mass spectrometry. An excellent correlation between PARP-1 inhibition in protein extracts and the ability of the complexes to bind to the zinc-finger motif (in competition with zinc) was established. The results support a model whereby displacement of zinc from the PARP-1 zinc finger by other metal ions leads to decreased PARP-1 activity. In vitro combination studies of cisplatin with NAMI-A and RAPTA-T on different cancer cell lines (MCF7, A2780, and A2780cisR) showed that, in some cases, a synergistic effect is in operation.
authors.affiliation: Unidade de Ciências Químicas e Radiofarmacêuticas, Instituto Tecnológico e Nuclear, Estrada Nacional 10, 2686-953 Sacavém, Portugal.
authors.forename: Filipa
authors.initials: F
authors.lastname: Mendes
authors.forename: Michael
authors.initials: M
authors.lastname: Groessl
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Nazarov
authors.forename: Yury O
authors.initials: YO
authors.lastname: Tsybin
authors.forename: Gianni
authors.initials: G
authors.lastname: Sava
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D019216:Metals, Heavy / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019216:Metals, Heavy; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases